Initial trigger is not enough to determine a stem cell's fate
Disturbing a stem cell from its initial quiescent state was once
thought to taint its gold-standard properties. However, research
uncovering how a signaling pathway regulates stem cell behavior
reveals that stem cells, once activated, enter a window of time
during which they respond to their environment and retain their
ability to alter their developmental path.
Scientists led by Elaine Fuchs at The Rockefeller University have
found that the BMP, or bone morphogenetic protein, pathway needs to
be turned on and off at the right time and at the right place for
adult skin stem cells to become hair follicles.
"These stem cells preferentially become hair follicles, but are
capable of redirecting their developmental course and becoming skin
cells when needed; if epidermal skin stem cells are not around to
repair a
Rethinking destiny. When hair follicle stem cells lose their ability
to respond to BMP, they proliferate (top) and eventually form tumor-
like masses (bottom). No longer capable of differentiating into hair
follicles, cells from these masses can still re-route their
developmental agenda and become skin cells (green).
wound on the surface of the skin, these hair follicle stem cells
become reprogrammed to make epidermis," says lead author Kris
Kobielak, a former postdoc in Fuchs's lab.
At the time of this finding, Kobielak had been trying to understand
the role of BMP in the development of hair cells. Since its discovery
in 1965, the BMP pathway has been found to regulate cell
proliferation and differentiation in many tissues, including hair
follicle. But until now, researchers didn't know how it controls stem
cell behavior during the hair cycle.
In adult skin, each hair follicle contains a reservoir of stem cells
called the bulge. When the bulge receives the proper signals, the
stem cells begin to proliferate into progenitor cells and then
differentiate into hair follicles.
The researchers found that while BMP signaling must be on to keep
these cells in an undifferentiated state, it must be off for these
cells to become activated and begin proliferating. BMP signaling then
needs to be turned back on for these activated stem cells to
differentiate into hair follicles.
When the researchers inactivated the BMP pathway using conditional
inducible gene targeting in a mouse, the bulge expanded as the stem
cells proliferated, but these cells couldn't differentiate into hair
follicles because the key signal they needed to progress to the next
step of the cycle was lost. "This resulted in large tumor-like masses
of cells that retained many markers of follicle stem cells," says
Fuchs, who is Rebecca C. Lancefield Professor and head of the
Laboratory of Mammalian Cell Biology and Development at Rockefeller
and an investigator at the Howard Hughes Medical Institute.
Kobielak, now an assistant professor of pathology at the Center for
Stem Cell and Regenerative Medicine at the University of Southern
California, and his colleagues thought that these activated stem
cells would lose their ability to differentiate into other cell types
and repair wounds.
But what the group found was just the opposite. When they created a
skin wound deep enough to wipe out the epidermal stem cells
underneath it, some of the activated stem cells migrated up through
the skin, differentiated into skin cells and repaired the wound.
"This was a surprise for us because many people thought that
quiescence was a fundamental feature of follicle stem cells, and that
once activated, the proliferating progeny enter a lineage and become
irreversibly committed," says Fuchs. "But since the tumors persist
over months, and the activated follicle stem cells can repair wounds,
it suggests that follicle stem cells can retain their multipotency
and become reprogrammed even after becoming activated to progress to
a step where they would normally produce hair."
The research not only has implications for understanding how stem
cells can be harnessed for regenerative medicine, but may also help
explain how some forms of cancer develop.
The tumors seen in Kobielak's mice overexpress the sonic hedgehog
signaling pathway, which is implicated in basal cell carcinomas. This
finding suggests that this form of cancer may originate from hair
follicle stem cells. "Nobody has ever looked at whether decreased BMP
signaling is a feature of basal cell carcinomas," says Fuchs. "This
finding," she says, "at least merits future exploration of this."
Proceedings of the National Academy of Sciences 104(24): 10063-10068
(July 12, 2007)
http://newswire.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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